Disruption of EphA/ephrin-A signaling in the nigrostriatal system reduces dopaminergic innervation and dissociates behavioral responses to amphetamine and cocaine
Disruption of EphA/ephrin-A signaling in the nigrostriatal system reduces dopaminergic innervation and dissociates behavioral responses to amphetamine and cocaine
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DOI：
10.1016/j.mcn.2004.03.009
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发表时间：
2004-07-01
影响因子：
3.5
通讯作者：
Ibáñez, CF
中科院分区：
文献类型：
--
作者：
Sieber, BA;Kumin, A;Ibáñez, CF
我们已经研究了EphA/ephrin-A信号转导在黑质纹状体系统的发育和功能中的功能作用，通过在转基因小鼠的中枢神经系统中过表达可溶性的、宽范围的EphA受体拮抗剂。成年转基因小鼠黑质（SN）的总体积减少了30-40%，而多巴胺能神经元的数量没有可检测到的差异。使用荧光金逆行追踪纹状体，我们检测到40-50%的多巴胺能神经元的数量减少，可以追溯到这个结构在转基因小鼠，这表明，这些细胞的比例较低，能够达到纹状体后，EphA/ephrin-A信号中断。尽管如此，转基因小鼠纹状体中的总多巴胺含量与野生型相当。分析自发活动及其调节的药物治疗，刺激多巴胺能传递揭示了一个意想不到的分离安非他明和可卡因的行为反应。特别是，转基因小鼠对苯丙胺相对不敏感，而对可卡因保持正常的反应性，据我们所知，这是第一次报告的解离行为反应，这两种精神兴奋剂。总之，这些结果揭示了EphA/ephrin-A信号传导在中脑多巴胺能神经元的正常连接和功能中的意想不到的作用。(C)2004爱思唯尔公司All rights reserved.
We have investigated functional roles of EphA/ephrin-A signaling in the development and function of the nigrostriatal system by overexpressing a soluble, broad-range EphA receptor antagonist in the central nervous system of transgenic mice. Adult transgenic mice showed a 30-40% reduction in the total volume of the substantia nigra (SN) without detectable differences in the number of dopaminergic neurons. Using fluorogold retrograde tracing from the striatum, we detected a 40-50% reduction in the number of dopaminergic neurons that could be traced from this structure in transgenic mice, suggesting that, a lower proportion of these cells were able to reach the striatum after disruption of EphA/ephrin-A signaling. In spite of this, total dopamine content in the striatum of transgenic mice was comparable to wild type. Analysis of locomotor activity and its regulation by pharmacological treatments that stimulate dopaminergic transmission revealed an unexpected dissociation of the behavioral responses to amphetamine and cocaine. In particular, transgenic mice were relatively insensitive to amphetamine while retaining normal responsiveness to cocaine, which, to the best of our knowledge, represents the first report of a dissociation of the behavioral responses to these two psychostimulants. Together, these results reveal an unexpected role for EphA/ephrin-A signaling in the normal connectivity and function of midbrain dopaminergic neurons. (C) 2004 Elsevier Inc. All rights reserved.